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Objective: The present study aimed to identify epidemiological factors associated with the development of intraductal papillary mucinous neoplasms (IPMN) of the pancreas comparing patients after IPMN resection with population-based controls., Methods: Preoperative data of 811 patients undergoing pancreatic resection for IPMN were matched in a 1:1 ratio with a random sample of volunteers from the Study of Health in Pomerania, which showed no pancreatic cyst greater than 2 mm in magnetic resonance cholangiopancreaticography., Results: A total of 811 controls with a mean age of 61.9 years (standard deviation, 8.4 years) were matched to cases with a mean age of 66.1 years (standard deviation, 9.3 years). A previous history of pancreatitis, endocrine pancreatic insufficiency was significantly more frequent in IPMN patients compared with controls (P = 0.001). Moreover, adjusted data revealed that urogenital cancer (P = 0.034), colorectal cancer (P = 0.021), as well as first-degree family history of colorectal cancer (P = 0.001) were significantly more frequent in IPMN patients., Conclusions: A history of urogenital and colorectal cancer often coincides with IPMN, which have an indication for surgery and are associated with preoperative episodes of pancreatitis and with endocrine insufficiency. Prospective studies are needed to investigate the role of these factors in IPMN development., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Acinar cell carcinoma of the pancreas (pACC) forms a rare subgroup of pancreatic tumors. We report on our institutional experience with systemic first- and further-line therapy in patients with metastatic pACC and embed our findings in a review of the literature., Methods: Patients with stage IV pACC who started systemic treatment between 2008 and 2019 at our institution were identified via our institutional database. Clinical data were extracted from the patients' electronic data records. Survival times were calculated by the Kaplan-Meier method., Results: Six patients received a fluoropyrimidine- and oxaliplatin-containing first-line treatment, and 4 patients were started on gemcitabine-based protocols. Median progression-free survival was 4.8 months [95% confidence interval (CI), 3.3 to not available (n.a.)], and median overall survival was 15.3 months (95% CI, 10.1 to n.a.). Residual survival for second-line treatment was 2.1 months (95% CI, 1.3 to n.a.), although 1 patient experienced almost complete remission under targeted therapy., Conclusions: The most encouraging and deep responses result from poly-chemotherapy with leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), which seems to be the appropriate choice in fit patients. Gemcitabine monotherapy seems without substantial activity in pACC. Whenever possible, patients with pACC should be screened for targetable mutations., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The surgical treatment of pancreatic cancer (PDAC) has seen sweeping changes during the past 5 decades. Up to the middle of the 20th century resection rates were below 5%, but the numbers of curative resections for PDAC are now continuously increasing due to improved neoadjuvant treatment concepts as well as progress in surgical techniques and perioperative management. During the same period, mortality rates after pancreatic surgery have decreased considerably and are now less than 5%. One of the most important cornerstones of reduced mortality has been the concentration of PDAC surgery in specialized centers. In addition, the management of postoperative complications has improved greatly as a result of optimized interdisciplinary teamwork. Adjuvant chemotherapy has become the reference treatment in resected PDAC, achieving significantly prolonged survival. Moreover, the concept of borderline resectable PDAC has emerged to characterize tumors with increased risk for tumor-positive resection margins or worse outcome. The best treatment strategy for borderline resectable PDAC is currently under debate, whereas neoadjuvant therapy has become established as a beneficial treatment option for patients with locally advanced PDAC, enabling conversion surgery in up to 60% of cases. This review article summarizes the principal changes in PDAC surgery during the past 50 years.

Objectives: Maintaining or improving muscle mass and muscle strength is an important treatment goal in pancreatic cancer (PC) patients because of high risk of cachexia. Therefore, we assessed feasibility and effectivity of a 6-month progressive resistance training (RT) in PC patients within a randomized controlled trial., Methods: Sixty-five PC patients were randomly assigned to either supervised progressive RT (RT1), home-based RT (RT2), or usual care control group (CON). Both exercise groups performed training 2 times per week for 6 months. Muscle strength for knee, elbow, and hip extensors and flexors and cardiorespiratory fitness and body weight were assessed before and after the intervention period., Results: Of 65 patients, 43 patients were analyzed. Adherence rates were 64.1% (RT1) and 78.4% (RT2) of the prescribed training sessions. RT1 showed significant improvements in elbow flexor/extensor muscle strength and in maximal work load versus CON and RT2 (P < 0.05). Further, knee extensors were significantly improved for RT1 versus CON (P < 0.05). Body weight revealed no significant group differences over time., Conclusions: Progressive RT was feasible in PC patients and improved muscle strength with significant results for some muscle groups. Supervised RT seemed to be more effective than home-based RT.

Objective: The aim of the study was to investigate serum thymidine kinase 1 (S-TK) activity as a diagnostic and prognostic marker for patients with pancreatic ductal adenocarcinoma (PDAC)., Methods: Using the sensitive TK activity assay DiviTum, preoperative serum samples from 404 PDAC, 28 chronic pancreatitis, and 25 autoimmune pancreatitis patients and 83 healthy volunteers were analyzed. The preoperative S-TK activities of 54 PDAC patients who received neoadjuvant therapy (nTx) were also compared with those of 258 PDAC patients who did not receive nTx., Results: The preoperative S-TK activities of PDAC patients were significantly higher and discriminatory from autoimmune and chronic pancreatitis patients and control groups. The S-TK activity in PDAC patients was associated with overall survival. Patients with S-TK activity of less than 80 Du (DiviTum units)/L demonstrated median survival of 20.3 months with an estimated 18.0% 5-year survival rate; for S-TK activity of 80 Du/L or greater, median survival was 15.1 months with a 6.8% 5-year survival rate. For early-stage PDAC, these differences were even more pronounced. The S-TK activity in the nTx group was significantly higher than that in the group not receiving nTx., Conclusions: Pancreatic ductal adenocarcinomas reveal a significant increase in S-TK activity, which is associated with overall survival, especially in early tumor stages. Serum thymidine kinase 1 activity may be a useful parameter for monitoring nTx efficacy.

Objectives: Our aim was to establish and characterize a novel pancreatic ductal adenocarcinoma cell line from a patient in whom the origin of the invasive carcinoma could be traced back to the intraductal papillary mucinous neoplasm (IPMN) precursor lesion., Methods: The primary patient-derived tumor was propagated in immunocompromised mice for 2 generations and used to establish a continuous in vitro culture termed ASAN-PaCa. Transplantation to fertilized chicken eggs confirmed the tumorigenic potential in vivo. Molecular analyses included karyotyping, next-generation genomic sequencing, expression analysis of marker proteins, and mucin-profiling., Results: The analysis of marker proteins confirmed the epithelial nature of the established cell line, and revealed that the expression of the mucin MUC1 was higher than that of MUC2 and MUC5AC. ASAN-PaCa cells showed rapid in vitro and in vivo growth and multiple chromosomal aberrations. They harbored mutations in KRAS (Q61H), TP53 (Y220C), and RNF43 (I47V and L418M) but lacked either IPMN-specific GNAS or presumed pancreatic ductal adenocarcinoma-driving mutations in KRAS (codons 12/13), SMAD, and CDKN2A genes., Conclusions: ASAN-PaCa cell line represents a novel preclinical model of pancreatic adenocarcinoma arising in the background of IPMN, and offers an opportunity to study how further introduction of known driver mutations might contribute to pancreatic carcinogenesis.

Objectives: Structured follow-up after surgery for pancreatic ductal adenocarcinoma (PDAC) remains controversial and is currently not recommended due to a supposed lack of therapeutic consequences. Furthermore, it is not clear whether noncancer patients after pancreas resection need to be seen in the clinic on a regular basis. The present study analyzed how follow-up after pancreatic surgery affected postoperative treatment and long-term outcomes., Methods: Data of all postoperative visits in a specialized outpatient clinic for pancreatic diseases were analyzed for a 1-year period with regard to symptoms, diagnostic procedures, and therapeutic consequences., Results: Six hundred eighteen patients underwent 940 postoperative follow-ups. Nearly half of them needed a change of medication due to altered pancreatic function. In 74 (40%) of 184 resected PDAC patients, recurrence (local or systemic) was detected during follow-up, although only 19 of these had shown associated symptoms (26%). In all patients with recurrence, a cancer-directed treatment was induced. Eleven (69%) of 16 patients with isolated local recurrence were referred for reresection., Conclusions: Follow-up examinations are a substantial part of the clinical management after pancreas resections. Follow-up is particularly important for PDAC because recurrence is often asymptomatic, but its detection allows for therapeutic interventions and potentially improved prognosis. This should be implemented in future guidelines.

Objectives: Severe necrotizing pancreatitis (SNP) is a disease with relevant morbidity and mortality until today. No specific therapy is in sight. Central α2 agonists such as clonidine and dexmedetomidine are known to have anti-inflammatory effects though the cholinergic anti-inflammatory pathway and are implemented in the clinical routine as adjunct sedative drugs. Their potential effect on SNP has not yet been tested., Methods: Severe necrotizing pancreatitis was induced in male Wistar rats. Four treatment groups received either clonidine or dexmedetomidine before (prophylactic) or after induction of SNP (therapeutic). After 12 hours, pancreatic morphologic injury, systemic proinflammatory high-mobility group box 1 protein, and pancreatic and pulmonary myeloperoxidase levels were evaluated., Results: Severe necrotizing pancreatitis was fully established 12 hours after induction. "Prophylactic" and "therapeutic" administration of clonidine and dexmedetomidine reduced pancreatic morphologic injury (P < 0.05 vs SNP), serum proinflammatory high-mobility group box 1 protein (P < 0.0001 vs SNP), as well as pancreatic and pulmonary myeloperoxidase levels (P < 0.01 vs SNP)., Conclusions: Prophylactic and therapeutic applications of the central α2 agonists clonidine and dexmedetomidine are effective to attenuate local and systemic injury in experimental SNP and should be evaluated in the clinical setting.

Objectives: Total pancreatectomy (TP) is associated with postoperative endocrine and exocrine insufficiency. Especially, insulin therapy reduces quality of life and may lead to long-term complications. We review the literature with regard to the potential option of pancreas transplantation alone (PTA) after TP in patients with chronic pancreatitis or benign tumors., Methods: A MEDLINE search (1958-2013) using the terminologies pancreas transplantation, pancreas transplantation alone, total pancreatectomy, morbidity, mortality, insulin therapy, and quality of life was performed. In addition, the current book and congress publications were reviewed., Results: Total pancreatectomy after benign and borderline tumors as well as chronic pancreatitis is continuously increasing. Despite improvement of exogenous insulin therapy, more than 50% of these patients experience severe glucose control problems, which cause up to 50% long-term mortality. Pancreas transplantation alone can cure both endocrine and exocrine insufficiency and reduce the associated risks. The 3-year graft and patient survival rates after PTA are up to 73% and 100%, respectively., Conclusions: Pancreas transplantation alone after TP in patients with pancreatitis or benign tumors improves the recipient's quality of life and reduces long-term mortality. Considering the amount of available organs and potential candidates, PTA can be a treatment option for patients after TP with chronic pancreatitis or benign tumors.

Objectives: The endogenous immune response is influenced by the stimulation of the vagal nerve. Stimulation or ablation has a direct impact on the release of pro- and anti-inflammatory mediators. In the progression of acute pancreatitis from local to systemic disease, these mediators play a pivotal role. This study evaluates the effect of pharmacologic stimulation of the cholinergic system on pancreatic damage in experimental necrotizing pancreatitis., Methods: Experimental severe necrotizing pancreatitis was induced in male Wistar rats using the glycodeoxycholic acid model. Animals with acute pancreatitis (n = 6) were compared with animals with acute pancreatitis and prophylactic or therapeutic pharmacologic activation of the cholinergic system using nicotine, physostigmine, or neostigmine (n = 36). Twelve hours after the induction of acute pancreatitis, morphological damage as well as the myeloperoxidase levels of the pancreas and the serum levels of high-mobility group box 1 protein were evaluated., Results: Prophylactic and delayed therapeutic application of nicotine, physostigmine, or neostigmine significantly attenuated the severity of acute pancreatitis 12 hours after the induction of severe necrotizing pancreatitis compared with untreated controls as evaluated with histological scores, myeloperoxidase, and high-mobility group box 1 levels (P < 0.05)., Conclusions: Stimulation of the cholinergic system is useful to attenuate damage in experimental acute pancreatitis. Not only prophylactic but also delayed application was effective in the present study.

Objectives: Five percent of alcoholics develop an acute pancreatitis (AP). The mechanism leading to pancreatic injury is not yet understood. Microcirculatory disorders seem to play a pivotal role. The objective of this study was to compare alcoholic pancreatic injury in response to intravenous and intragastric routes of alcohol administration., Methods: Alcohol was applied in rats intravenously (IV) or gastric via a surgical implanted feeding tube (IG). Serum alcohol concentration was maintained between 1.5‰ and 2.5‰. Four subgroups (n = 6/group) were examined in the IV/IG arm and compared with healthy controls. Pancreatic microcirculation, enzyme levels, and morphological damage were assessed after 3, 6, 12, and 24 hours., Results: Microcirculatory analysis showed significantly disturbed pancreatic perfusion and increased adherent leukocytes in IV and IG animals. In IV and IG groups, serum amylase was increased without morphological signs of AP compared with healthy controls., Conclusions: Alcohol application does not induce AP in rodents, but impairs pancreatic microcirculation irrespectively of the application route. Intravenous application is commonly used and shows no disadvantages compared with the physiological intragastric application form. Therefore, the intravenous route offers a valid model, which mimics the physiological process for further studies of the influence of acute alcohol intoxication on the pancreas.

Objectives: To investigate the incidence, characteristics, and prognostic impact of prior extrapancreatic malignancies on patients with pancreatic cancer (PDAC)., Methods: Records from 1733 patients who underwent surgery for PDAC were analyzed for the occurrence of prior extrapancreatic malignancies. Patients' records showing extrapancreatic malignancies were then analyzed for tumor type, epidemiological data, risk factors, PDAC tumor stage, and long-term survival., Results: A total of 239 patients with PDAC (13.8%) had a history of 271 extrapancreatic tumors; 26 patients had a history of two pancreatic cancers, and 3 patients had 3 extrapancreatic cancers. The most common extrapancreatic tumors were breast cancer (56 patients) and prostate cancer (41 patients), followed by colorectal, reno/urothelial, and gynecologic tumors (39, 32, and 23 patients, respectively). No significant difference in overall survival was found between patients with PDAC with or without extrapancreatic malignancies., Conclusions: Pancreatic cancer is associated with extrapancreatic malignancies in a remarkable number of patients. A history of extrapancreatic malignancies does not influence prognosis and should not be an obstacle to a curative therapeutic approach. Surveillance of patients with extrapancreatic malignancies, especially breast, prostate, and colorectal cancer, could allow for earlier PDAC diagnosis and therefore improve prognosis of these patients.

Objective: Systemic complications in alcoholic pancreatitis are supposed to be aggravated by inflammatory liver damage. Resident macrophages including hepatic Kupffer cells play a pivotal role in mediating systemic complications in severe necrotizing pancreatitis (SNP). The aim of this study was to evaluate the effects of Kupffer cell inhibition on the inflammatory liver damage in experimental alcoholic pancreatitis., Methods: Rats were fed with either alcohol or control diet for 6 weeks before induction of SNP. Animals were allocated into 4 groups: healthy controls, controls with SNP, SNP with gadolinium chloride or glycine (permanent vs temporary inhibition of hepatic Kupffer cells) prophylaxis. Hepatic microcirculation and morphologic damage of the liver and pancreas were assessed., Results: Alcohol feeding and SNP increased hepatic and pancreatic injury compared with SNP alone. Gadolinium chloride and glycine improved hepatic microcirculation. In contrast, pancreatic and hepatic morphological damage was reduced by gadolinium chloride but not by glycine., Conclusions: Alcohol exposure aggravates hepatic and pancreatic injury in SNP. Gadolinium chloride reduces both microcirculatory and morphological damage, whereas glycine did not improve histological damage.

Objectives: Calcitonin gene-related peptide (CGRP) is released from perivascular pancreatic nerves. It effects vasomotion and cytokine liberation in inflammatory processes, including acute pancreatitis (AP). Calcitonin gene-related peptide liberation is stimulated by capsaicin, a substance of red hot chili peppers. Aim of the study was to investigate the influence of exogenous capsaicin on experimental AP., Methods: Acute pancreatitis was induced in rats by glycodeoxycholic acid and cerulein. Animals were divided into 4 groups: (1) severe AP, (2) severe AP+capsaicin, (3) control without AP, and (4) control+capsaicin. After 24 hours, survival, histology, and CGRP were evaluated (n=6/group). In additional animals, erythrocyte flow and leukocyte activation were evaluated by intravital microscopy 6 hours after AP induction (n=6/group)., Results: In the control groups, all animals survived without histological alterations. Mortality in severe AP was 67%. Capsaicin reduced mortality to 16% (P<0.05). Acute pancreatitis animals developed pancreatic inflammation and necrosis, which was significantly less after capsaicin application. Intravital microscopy in severe AP showed reduced erythrocyte velocity and increased leukocyte adhesion, which was nearly normalized by capsaicin (P<0.01). Calcitonin gene-related peptide increased in both capsaicin groups, indicating endogenous CGRP liberation (P<0.01)., Conclusion: Capsaicin releases endogenous CGRP with improved pancreatic microcirculation and reduced inflammation in experimental AP. This underlines neuropeptide activity in the pathogenesis of AP.

Objectives: Ischemia reperfusion (I/R)-associated early graft pancreatitis is a major complication after pancreas transplantation. The influence of immunosuppressants on graft pancreatitis remains unclear. The aim of this study was to evaluate ciclosporin and tacrolimus in experimental pancreatic I/R., Methods: Moderate pancreatitis was induced in rats by I/R injury. Animals were assigned to 4 groups: (1) control without I/R, (2) I/R without therapy, (3) I/R + ciclosporin, or (4) I/R + tacrolimus. After 24 hours, pancreatic damage was evaluated by amylase, endothelin 1, thromboxane A2, and histology. Additionally, microcirculation was evaluated 12 hours after reperfusion by intravital microscopy., Results: I/R significantly increased amylase compared with controls, with maximum levels after ciclosporin treatment. Histology showed comparable tissue injury in control and tacrolimus-treated animals. Ciclosporin-treated animals developed significantly (P < 0.05) more inflammation and necrosis compared with the other groups. Erythrocyte velocity evaluated by intravital microscopy was reduced in all animals after I/R. This was significantly pronounced after ciclosporin application. There was a significant increase of adherent leukocytes and platelets in ciclosporin-treated animals compared with both other groups., Conclusions: Tacrolimus does not negatively influence I/R-induced pancreatitis, whereas ciclosporin aggravates pancreatic tissue damage after I/R. These effects should be evaluated in the clinical setting of pancreas transplantation.